The present invention relates to a new compound which we have named "Leualacin" and which may be produced by fermentation using appropriate strains of microorganisms of the genus Hapsidospora, especially Hapsidospora irregularis. The invention also provides processes for the production of this new compound as well as compositions and methods using it for the treatment and prophylaxis of cardiovascular diseases and disorders. It also discloses a strain of microorganism of the species Hapsidospora irregularis, which may be used to produce the new compound.
It is now well established that the influx of calcium ions into certain cells in the mammalian body, including the smooth muscle cells of the vascular system and the myocardial cells, participates in the activity of such cells and that the dihydropyridine-sensitive calcium channel, which is situated on the cell surfaces of skeletal muscles and the myocardium, plays a role in regulating the influx of calcium ions into the cells. Hence, the administration of calcium channel blockers (also known as calcium antagonists), which inhibit such influx, would suppresses myocardial contractile force and rate and cause vasodilation. The calcium channel blockers are, therefore, useful in the treatment and prophylaxis of a variety of diseases and disorders of the heart and vascular system, such as angina pectoris, myocardial infarction, arrhythmia, hypertension, cerebrovascular spasm and other ischemic diseases and disorders.
It has been disclosed that verapamil (trade name "VASOLAN", a product of Eisai Co., Ltd.) and other calcium channel blockers inhibit the binding of .sup.3 H-nitrendipine to the calcium channels of the cell membrane. It is, therefore, thought that other substances that inhibit the binding of nitrendipine to the calcium channel of the cell membrane might also be useful as calcium channel blockers. As a result of its blocking the calcium channels, a calcium channel blocker suppresses any increase in intracellular calcium concentration and protects the patient against coronary spasm and dilation of the blood vessels.
A number of compounds having calcium channel blocking activity is known, for example certain dihydropyridine derivatives, such as nifedipine (trade name "ADALAT", a product of Bayer Yakuhin Co.. Ltd.) and nicardipine, and other compounds, such as verapamil (mentioned above), diltiazem and flunarizine. Of these, nifedipine, nicardipine and diltiazem are widely used but are structurally unrelated to the compounds of the present invention. Verapamil and flunarizine are also structurally unrelated to the compounds of the present invention. Moreover, all of these known compounds are chemically synthesized compounds, whereas the compound of the present invention is a "natural" product, in that it is the product of fermentation. Only one prior "natural" product is known to us to have calcium antagonist activity, and that, like the compound of the present invention, is a cyclic peptide. This known compound is Scytonemin A. which was disclosed in the Journal of Organic Chemistry, 53, 1298-1307 (1988), but this compound has not yet been used clinically. Moreover, although it is a cyclic peptide, it has, as can be seen from the aforesaid article, a wholly different structure from that of the compound of the present invention and it is produced by a blue-green alga of the genus Scytomenin, whereas the compound of the present invention is produced by a mold of the genus Hapsidospora.